Urinary incontinence is a clinical condition characterized by failure to hold urine in the bladder under normal conditions of pressure and filling. Urinary incontinence afflicts an estimated 13 million Americans. A 1980 British postal survey of 22,430 people showed a prevalence of urinary incontinence of 8.5% in women and 1.6% in men aged 15-64, and 11.6% in women and 6.9% in men aged 65 and over.
Six of every seven adult incontinence cases occur in women; 15% to 30% of women experience incontinence during their lifetimes. Women are more at risk than men because of pelvic nerve trauma during childbirth and the comparative shortness of the female urethra (around two inches versus ten in men). Women who have their first child when over age 30 or who use the drug oxytocin for inducing labor appear to be at increased risk for urinary incontinence later on. (Such medically-induced labor tends to subject pelvic muscles and nerves to greater forces than does natural labor.) In addition, women who perform high-impact exercise, such as gymnasts, and softball, volleyball, and basketball players, are susceptible to urinary leakage, particularly those with a low foot arch, which, on impact, increases the shock to the pelvic area. In addition, a study of 600 women found that smokers and former smokers are twice as likely to develop incontinence than are women who never smoked. According to one 1999 study, urge incontinence is more common among older postmenopausal women who are diabetic or who reported two urinary tract infections within the past year. Obesity is also a major factor for incontinence in older women.
Forms of Urinary Incontinence
The most common forms of urinary incontinence can arise from either a failure of muscles around the bladder neck and urethra to maintain closure of the urinary outlet (so-called stress incontinence) or from abnormally heightened commands from the spinal cord to the bladder that produce unanticipated bladder contractions (so-called urge incontinence). Patients with stress incontinence experience minor leakage from activities that apply pressure to a full bladder, such as coughing, sneezing, laughing, running, lifting, or even standing. People with urge incontinence (also called hyperactive or irritable bladder) need to urinate frequently or are unable to reach the bathroom before leakage. When the bladder reaches capacity, the nerves appropriately signal the brain that the bladder is full, but the urge to void cannot be voluntarily suppressed—even temporarily. In a variant type of urge incontinence called reflex incontinence, the sensation of fullness is not adequately communicated to the brain, and in the absence of the brain's inhibition of this automatic process, the bladder releases urine.
Another common form of the disorder is overflow incontinence, which results when the bladder cannot empty completely, generally because of a partial obstruction or an inactive bladder muscle. In contrast to urge incontinence, the bladder is less active than normal. It cannot empty properly and so becomes distended. Eventually this distention stretches the internal sphincter until it opens partially and leakage occurs. Functional, or environmental, incontinence encompasses a variety of conditions in which the patient is unable to use the bathroom because of physical or emotional impairments. Approximately 40% of incontinence patients fall into more than one of these four categories (stress, urge, overflow, and functional incontinence), and experience so-called mixed incontinence.
Anatomy and Physiology of the Lower Urinary Tract
The urinary bladder is composed of smooth muscle collectively referred to as the detrusor muscle. Smooth muscle of the urethra is contiguous with the detrusor muscle and is referred to as the internal urethral sphincter, although it is not a true anatomic sphincter. Skeletal muscle surrounding the urethra is called the external urethral sphincter.
Innervation of the lower urinary tract is complex. Tight junctions between bladder smooth muscle cells allow for transmission of nerve impulses from cell to cell. The hypogastric nerve, originating from spinal cord segments of L1 through L4, supplies sympathetic innervation to the bladder and urethra. The pelvic nerve, originating from the spinal cord segments S1 through S3, supplies parasympathetic (cholinergic) innervation to the detrusor muscle and transmits sensory impulses from the bladder. Somatic innervation of the muscle of the external urethral sphincter is distributed via the pudendal nerve, originating from spinal cord segments S1 through S3. The pudendal nerve also innervates muscles of the anal sphincter and perineal region, and it also transmits sensation from the perineal region and the urethral and anal sphincters.
The sympathetic and somatic nervous systems dominate the storage phase of micturition. Sympathetic stimulation of beta-adrenergic receptors in the detrusor muscle results in bladder relaxation to accommodate filling. Sympathetic stimulation of alpha-adrenergic receptors in the neck of the bladder and internal urethral sphincter maintains continence. Sympathetic pathways also inhibit parasympathetic bladder innervation during storage. Stimulation of the pudendal nerve results in increased tone of the external urethral sphincter, contributing to continence. When the bladder is full, sensation is transmitted via the pelvic nerve to the sacral spinal cord, and subsequently the brainstem. Voluntary control of urination originates from the cerebral cortex. The storage phase of the urinary bladder can be switched to the voiding phase either voluntarily or involuntarily (reflexively).
Signals to the cortical center generally occur when bladder volume has reached 250 mL to 300 mL. When urination is desired, neural impulses from the cortex are transmitted through the spinal cord and pelvic nerves to the detrusor muscle. Daytime emptying of the bladder may occur as often as every few hours or as infrequently as every 8 to 12 hours. During the emptying phase of micturition, parasympathetic (cholinergic) activity of the pelvic nerves causes the detrusor muscle to contract and the bladder to empty. Simultaneous inhibition of sympathetic and somatic stimulation of the urethral smooth and skeletal muscle results in urethral relaxation. Following complete emptying of the bladder or voluntary cessation of urination, the storage phase begins again. External urethral sphincter tone can increase in response to sudden increases in abdominal pressure (e.g., during coughing) to maintain continence. Disruption of tight junctions, peripheral nerves, spinal cord segments, or higher brain centers may alter micturition.
Reflex Arcs in the Lower Urinary Tract
The function of the lower urinary tract is modulated by several reflex arcs. The most prominent of these is a positive feedback reflex that modulates micturition. Mechanoreceptors in the bladder are distended when the bladder is at capacity, and they trigger a coordinated micturition reflex via a center in the upper pons and perhaps through a spinal reflex as well. The bladder contracts, causing an even greater distention of the mechanoreceptors, leading to even greater activation of the micturition reflex and bladder contraction. This ensures that the bladder is completely emptied during normal voiding.
Other lower urinary tract reflexes are inhibitory. The external urethral sphincter is reflexively activated by mechanoreceptors during bladder filling, so that sphincter pressure increases as needed. Anal dilatation has been demonstrated to reflexively inhibit detrusor contraction, thereby preventing involuntary urine leakage during defecation. Gentle mechanical stimulation of the genital and perineal regions also reflexively inhibits detrusor contraction, thereby preventing involuntary urine leakage during sexual stimulation and coitus. The afferent portions of these reflex arcs are carried by the pudendal nerve, which carries somatic sensory information from the pelvic floor, and the pelvic nerve, which carries much of the pelvic visceral sensations. Bladder contraction is also reflexively inhibited by the activation of stretch fibers in pelvic and limb muscles, thereby preventing involuntary urine leakage during physical activity.
Neurologic Causes of Incontinence
Urinary incontinence may be associated with neurologic disease. Neurologic abnormalities may disrupt the detrusor muscle, urethral sphincters, or both. Neurologic incontinence may result from trauma, tumors, or herniated intervertebral discs. The location of the lesion will dictate the type of micturition disorder and other concurrent neurologic abnormalities.
Patients with upper motor neuron (UMN) lesions—those above the sacral spinal cord segments—lack voluntary control of micturition. Urination may be initiated by spinal reflexes, but an absence of sensation and central nervous system control, and the failure of the sphincters to relax, leads to interrupted, involuntary, and/or incomplete voiding. Manual bladder expression is difficult if sphincter hypertonia is present, but the urethra can be catheterized normally. Overflow of urine occurs when the bladder pressure exceeds sphincter resistance. The perineal reflex is intact.
Detrusor instability (a.k.a. detrusor areflexia) with decreased sphincter tone results from disease of sacral spinal cord segments or bilateral lesions of the sacral spinal nerve roots (i.e., lower motor neuron, or LMN, lesions). Voluntary control of urination is absent. Fecal incontinence may also be present, and perineal reflexes may be absent. Detrusor instability may also occur secondary to prolonged overdistention of the bladder. Tight junctions between muscle cells are disrupted, preventing spread of nerve impulses. The patient will attempt to void because sensory pathways are intact, but the atonic, flaccid bladder is unable to contract. Residual urine volume is large.
Reflex dyssynergia occurs with incomplete spinal cord lesions cranial to the sacral spinal cord segments. The detrusor reflex is normal to hyperactive, and the urethral sphincters are hyperactive. The patient voluntarily initiates urination, but the urine stream is abruptly stopped because there is synchronization between bladder contraction and urethral relaxation, leading to incomplete voiding. Urethral obstruction can result in a similar pattern of micturition. Cerebral lesions may also result in the loss of voluntary control of micturition.
Causes of Urge Incontinence
The most common cause of urge incontinence is detrusor instability, where patients have involuntary detrusor contractions that are non-neuropathic or of unknown origin. There is no general consensus regarding the cause of detrusor instability although both a myogenic and neurologic basis have been suggested.
Detrusor instability occurs in about 75% of men with benign prostatic hyperplasia and causes frequency, urgency, and urination during the night, although incontinence itself occurs only in very severe cases. Surgical procedures, such as prostatectomy and transurethral resection of the prostate (TURP), can cause detrusor instability. Incontinence rates in TURP are very low (about 1%) but they can be significant after prostatectomy. (In the latter case, detrusor instability is usually only one of many factors involved in incontinence.)
The other common cause of overactive bladder muscle abnormalities and urge incontinence is detrusor hyperreflexia. Involuntary detrusor contractions caused by detrusor hyperreflexia may result from a central nervous system (CNS) impaired by known neurologic conditions such as stroke, multiple sclerosis, spinal cord or disk injury, dementia, or Parkinson's disease. These conditions can result in detrusor hyperactivity by interfering with the normal flow of nerve messages between the urinary system and the CNS.
Urge incontinence results from bladder contractions that overwhelm the ability of the cerebral centers to inhibit them. These uncontrollable contractions can occur because of inflammation or irritation of the bladder from calculi, malignancy, infection, atrophic vaginitis, or urethritis. Drugs that may cause or contribute to urge incontinence include diuretics and caffeine (which increase urine flow), sedative hypnotics or narcotics (which depress micturition centers in the brain), and alcohol (which also inhibits micturition centers in the brain and has a diuretic effect). Uncontrollable contractions can also occur when brain centers that inhibit contractions are inhibited by metabolic disorders such as hypoxemia and encephalopathy. Anxiety and normal aging can also cause the bladder to become overactive. Some evidence suggests that some cases are caused by ischemia (blockage of blood vessels), the same process that leads to coronary artery disease.
Disorders of the cortex may result in an overactive bladder. Functional brain scanning in healthy volunteers during micturition has demonstrated that specific areas of the frontal cortex may be involved in the micturition process. These areas have demonstrated reduced activity in elderly patients with urge incontinence.
Pathophyslology of Urge Incontinence
In a number of patients with urgency, frequency, and/or urge incontinence, the pathological process may somehow be initiated by a sustained or prolonged nociceptive signal via the somatic and/or visceral afferents (due to an underlying process such as myofascial pain or endometriosis). A prolonged nociceptive signal is believed to cause biochemical and neuropathic changes within the spinal cord, perhaps through reflexive activity within the bladder and other pelvic tissues. This process has been referred to as neurogenic inflammation, in which a neuroinflammatory process is believed to be mediated by release of vasoactive peptides such as substance P and neurokinin A.
“Neurogenic inflammation is the process whereby stimulation of peripheral nerves elicits vasodilatation, plasma extravasation, and other inflammatory changes in the skin or viscera. Neurogenic inflammation can be evoked in the bladder by antidromic stimulation of visceral afferents in the pelvic nerve. Although bladder afferents relay information to the central nervous system, they also act in the periphery to alter mucosal permeability, smooth muscle contractility, local blood flow and to influence cellular mediators of the immune system; thus an initial inflammatory event may be reinforced by neurogenic mechanisms. The resulting changes in neural processing affect the pain pathways in particular, and perturbations in the function of peripheral and central elements of the nociceptive system can be durable, outlasting the initial inflammation.” [Steers W D; Tuttle J B. “Chapter 8: Neurogenic Inflammation and Nerve Growth Factor: Possible Roles in Interstitial Cystitis”, in Sant G R, ed., Interstitial Cystitis, Lippincott Williams & Wilkins, 1997.]
With changes in spinal reflexes and the “centralization of pain,” the neuropathic changes within the spinal cord become so pronounced that even with the removal of external insult, e.g., treatment of endometriosis, the neuropathic dysregulation persists. This neuropathic change explains why patients with a chronic pelvic pain syndrome may present with multiple overlapping symptoms that frequently involve pelvic pain, urgency/frequency syndrome, urge incontinence, fecal incontinence, functional bowel disease, dyspareunia, vestibulitis, and/or dysfunctional voiding.
Current Treatments
There are many surgical procedures for urinary incontinence; most are designed so pressure is exerted effectively at the neck of the bladder. The four primary procedures are retropubic suspensions (about 80% cure rate), transvaginal suspensions (60-70% cure rate), sling procedures (about 80% cure rate), and anterior repairs (60-70% cure rate). Suspensions have higher complication rates than the other procedures. Studies reported by the American Urological Association indicated that surgery should be considered as initial therapy for women with severe stress incontinence and that surgery is an effective and safe alternative when other treatments fail. Potential complications of all of these surgical procedures include obstruction of the outlet from the bladder, which causes difficulty in urination and irritation. Surgery is typically not performed in individuals with urge incontinence who have uninhibited bladder contractions.
Injections of bulking materials that help support the urethra are proving to be beneficial for people with severe stress incontinence caused by dysfunctional sphincter muscles in the urethra, but who still have good pelvic muscle support and functional bladders. The bulking agent most commonly used today is collagen, specifically animal collagen (Contigen). The collagen is injected into the tissue surrounding the urethra. The injected collagen tightens the seal of the sphincter by adding bulk to the surrounding tissue.
It is well known in the art that electrical stimulation in the region of the pelvic floor can decrease the severity of incontinence. The improvement is believed to be attained through at least three mechanisms: (1) by changing the reflex thresholds of the bladder muscles responsible for bladder emptying, (2) by strengthening the muscles that maintain closure on the bladder outlet, and (3) by changing the state of the neural pathways, musculature and/or bladder during and beyond the period of stimulus application.
The electrical stimulation therapies currently available for incontinence have generally been directed at improving muscle condition, as disclosed, e.g., in applicant's prior document WO97/18857 (PCT/US96/18680), published 29 May 1997. Bladder hyperreflexia and detrusor instability have proven more difficult to treat. However, evidence in the art suggests that it can be improved in many individuals by stimulating peripheral nerves or nerve roots continuously or intermittently to modulate transmission of excitatory nerve signals to the bladder muscles.
Several external and implantable approaches have been used to stimulate the nerves supplying the bladder and pelvic region in order to decrease the episodic incidences of unintentional bladder emptying. The approaches that strengthen periurethral muscles have usually employed vaginal or anal electrode assemblages to stimulate muscle contractions repeatedly. These methods are limited in their portability and are often poorly accepted by patients because they are inconvenient and often associated with unpleasant skin sensations. Further, the methods are inadequate for the treatment of urge incontinence in which continual electrical stimulation is commonly needed to diminish or inhibit the heightened reflexes of bladder muscles.
For the treatment of urge incontinence, surgically implanted stimulators under battery or radio-frequency control have been described in the art. These stimulators have different forms, but are usually comprised of an implantable control module to which is connected a series of leads that must be routed to nerve bundles in either the sacral roots emanating from the spinal cord, or the nerves supplying muscles, skin or other structures in the pelvic region. The implantable devices are relatively large, expensive and challenging to implant surgically. Thus, their use has generally been confined to patients with severe symptoms and the capacity to finance the surgery.
In one study, a vaginal device employing electrical stimulation was significantly more effective than a sham device for patients with urge incontinence, although there was no difference for women with stress incontinence. The Stoller Afferent Neural Stimulator (SANS) device has been applied to stimulation of the nerves above the ankle bone; more than 75% of mild to moderate incontinence patients treated in this way once a week for about a half hour reported at least 50% reduction in symptoms.
Sacral Nerve Stimulation
A sacral nerve stimulation (SNS) system (Medtronic InterStim) is available for urge incontinence, in which a battery-operated generator that produces electrical pulses is implanted in the abdomen. A wire connected to it runs to the sacral nerves in the lower back. The Sacral Nerve Stimulation Study Group compared 34 incontinence patients receiving SNS with 42 control patients who received standard medical therapy. (Reference Schmidt, et al., “Sacral nerve stimulation for treatment of refractory urinary urge incontinence. Sacral Nerve Stimulation Study Group.” Journal of Urology, 1999 August; 162(2):352-7.)
At 6 months, the number of daily incontinence episodes, severity of episodes, and use of absorbent pads were significantly reduced in the stimulation group compared to the control group. Of the 34 SNS patients, 16 (47%) were completely dry and an additional 10 (29%) demonstrated a greater than 50% reduction in incontinence episodes six months after implantation. Efficacy appeared to be sustained for 18 months. During the evaluation, the group returned to baseline levels of incontinence when stimulation was inactivated. Urodynamic testing confirmed that SNS did not adversely affect voiding function. Complications included implantable pulse generator site pain in 15.9% of the patients, implant site pain in 19.1% and lead migration in 7.0%. Surgical revision was required in 32.5% of patients with implants to resolve a complication. There were no reports of permanent injury or nerve damage.
Shaker applied SNS to 16 women and 2 men with refractory urge incontinence. (See Shaker, et al., “Sacral nerve root neuromodulation: an effective treatment for refractory urge incontinence.” Journal of Urology 1998 May; 159(5):1516-9.) Over an average follow-up period of 18.8 months (range 3 to 83), these patients showed a marked reduction in leakage episodes from 6.49 to 1.98 times per 24 hours. Eight patients became completely dry and 4 had average leakage episodes of 1 or less daily. Patients also demonstrated a decrease in urinary frequency with an increase in functional bladder capacity. Associated pelvic pain also decreased substantially.
The mechanism of action of sacral nerve stimulation is unknown. The afferent somatic stimulation is believed to somehow modulate the neural reflexes involved in micturition, thereby inhibiting micturition. The same inhibitory action is also believed to be responsible for the control of fecal incontinence by SNS, as described in more detail presently. SNS leads to stimulation of one or more sacral dorsal ganglia, which may also help control somatic and/or visceral pelvic pain through the same mechanism of action as spinal cord stimulation (SCS). (In SCS the non-nociceptive afferent signals are believed to “gate” or otherwise modulate central processing of nociceptive signals, via the gate control theory.) SNS may also stimulate the pelvic floor musculature and may be a form of biofeedback, enabling its use in pelvic floor rehabilitation. During typical SNS system implantation, pudendal nerve recruitment is targeted, and may be confirmed by contractions in the pelvic floor.
Malouf reported on implantation of chronic SNS systems in five women (age 41-68 years) with fecal incontinence for solid or liquid stool at least once per week. (Reference Malouf, et al., “Permanent Sacral Nerve Stimulation for Fecal Incontinence.” Annals of Surgery 2000 July; 232(1):143-148.) These patients were followed up for a median of 16 months after permanent implantation. All had incontinence, and three had urge incontinence. The cause was scleroderma in two, primary internal sphincter degeneration in one, diffuse weakness of both sphincters in one, and disruption of both sphincters in one. All patients had marked improvement. Urgency resolved in all three patients with this symptom. Passive soiling resolved completely in three and was reduced to minor episodes in two. Continence scores (scale 0-20) improved from a median of 16 before surgery to 2 after surgery. There were no early complications, and there have been no side effects. One patient required wound exploration at 6 months for local pain, and a lead replacement at 12 months for electrode displacement. The quality of life assessment improved in all patients. The resting pressure increased in four patients, but there was no consistent measured physiologic change that could account for the symptomatic improvement.
Pudendal Nerve Stimulation
Bladder contraction and micturition may be inhibited through a number of reflex arcs, some involving afferent fibers of the pudendal nerve, as discussed above. Distal branches of the pudendal nerve lead to the anal sphincter, the perineum, the urethral sphincter, the penis (in men), the vagina (in women), the glans penis (in men), and the clitoris (in women). Stimulation of the pudendal afferents from the anal sphincter has been demonstrated to inhibit bladder contraction. Similarly, stimulation of the pudendal afferents from the dorsal nerve of the penis (in men) or the dorsal nerve of the clitoris (in women) has been demonstrated to inhibit bladder contraction.
In 1974, Sundin, et al. demonstrated in cats that acute electrical stimulation of the pudendal nerve leads to detrusor inhibition. (See Sundin, et al., “Detrusor inhibition induced from mechanical stimulation of the anal region and from electrical stimulation of pudendal nerve afferents: An experimental study in cats” Investigative Urology, 1974 March; 11(5):374-8.) In 1986, Vodusek, et al. demonstrated in 8 male and 2 female patients that stimulation of the dorsal nerve of the penis or the dorsal nerve of the clitoris with surface electrodes led to bladder inhibition and an increase in bladder capacity in 8 of the 10 patients. (Reference Vodusek, et al., “Detrusor inhibition induced by stimulation of pudendal nerve afferents” Neurourology and Urodynamics, 5, 1986, 381-9.) The authors concluded that stimulation of the pudendal nerve afferents leads to detrusor inhibition in patients with neurological lesions above the sacral level.
In a 1988 study of three patients with urgency, frequency, and urge incontinence, Vodusek, et al. demonstrated that acute percutaneous electrical stimulation of the pudendal nerve at the ischial spine led to inhibition of bladder contraction and to a two- to four-fold increase in bladder capacity. The neurostimulation waveform had a frequency of 1 to 5 Hz, an amplitude of 1 to 2 mA, and a pulse width of 200 μsec. Activation of the external urethral sphincter via the efferent fibers of the pudendal nerve may also have played a role in the observed increase in bladder capacity. (See Vodusek, et al., “Detrusor inhibition on selective pudendal nerve stimulation in the perineum” Neurourology and Urodynamics. 6, 1988, 389-93.)
U.S. Pat. No. 4,607,639 (the '639 patent) discloses a method for controlling bladder evacuation via electrical stimulation of sacral roots and/or pelvic floor nerves, including the pudendal nerve. However, this method requires, first, the arduous task of, for example, “identifying the anatomical location and functional characteristics of those nerve fibers controlling the separate functions of said bladder and external sphincter.” This identification is accomplished via a sacral route. Next, separating motor and sensory and/or somatic and autonomic nerve fibers is taught. Again, nerve fiber separation is accomplished via a sacral route. Additionally or alternatively to the separating of nerve fibers, the method requires isolating nerve fibers via sectioning. Again, nerve fibers are sectioned via a sacral route.
The '639 patent indicates that the method includes “identifying the anatomical location of at least one nerve.” However, since one or a combination of separating, sectioning, and stimulating at least two separate nerve fibers is described, it is clear from a careful reading that the method taught in the '639 patent requires locating and identifying at least two separate neural structures. For example, one of the specific procedures of the '639 patent requires identification of both the superior somatic nerve (which innervates the levator ani muscles) and the inferior somatic nerve (innervating the pudendal nerve at Alcock's canal), so that the superior somatic nerve may be sectioned and the inferior somatic nerve may be stimulated. As another example, the S3 sacral nerve is identified, then the ventral and dorsal roots are surgically separated (which requires their identification), so the ventral root alone may be stimulated. Other specific procedures require the stimulation of at least two separate neural structures, such as the inferior somatic nerve and the S3 ventral root (separated from the dorsal root). Such procedures may reasonably be expected to be more time-consuming than the identification and stimulation of a single neural structure. The '639 patent does not teach a method in which identification of only one neural structure is necessary, e.g., identification of a single nerve such as the pudendal nerve, which directly controls the function of the external sphincter and not the bladder.
Further, all the surgical procedures described in the '639 patent are performed via a sacral approach. A plethora of pelvic area nerves emanate from the sacral segments. Therefore, stimulation of the neural structures targeted by the '639 patent via a sacral route results in 1) needing to identify which nerves to stimulate, separate, or section, and 2) the actual separating and sectioning of physically and/or physiologically close nerve fibers. Thus, it is not surprising that the surgical procedures of the '639 patent are complicated by the identifying, separating, and sectioning of multiple nerves. In addition, it is difficult or impossible to reach portions of some nerves via a sacral approach, such as the portion of the pudendal nerve that passes through Alcock's canal.
Additionally, the '639 patent describes only radio-frequency control of an implanted stimulating electrode.
Many of the therapies described above have been used to treat pelvic pain, with the same drawbacks. For instance, neurostimulation of the sacral nerve roots has been demonstrated to relieve pelvic pain in patients with intractable chronic pelvic pain. Other devices used for both incontinence and pelvic pain require that a needle electrode(s) be inserted through the skin during stimulation sessions. These devices may only be used acutely, and may cause significant discomfort.
What is needed are ways to effectively use implantable stimulators to chronically stimulate the pudendal nerve and its branches directly, for treating incontinence and/or pelvic pain.